Explanation When ingested orally, ascorbic acid is tightly controlled by three physiologic mechanisms: absorption, tissue transport, and renal reabsorption/excretion. Intravenous administration of ascorbic acid bypasses tight control until the kidney restores homeostasis, as determined from bioavailability experiments conducted by this laboratory. These data have surprising and novel implications for cancer treatment. More than 30 years ago, Ewan Cameron proposed that ascorbic acid might have a beneficial effect in treating patients with cancer. Joined by the two-time Nobel Laureate Linus Pauling, they published two case series indicating potential benefit of a large daily dose of ascorbic acid, 10 grams, in some patients with terminal cancer. Note for comparison purposes that the recommended dietary allowance for ascorbic acid at that time was 60 mg daily, or 0.6% of the treating dose. The Cameron-Pauling data were criticized because they were retrospective, without placebo control, in part subjective, and lacked independent pathologic confirmation. Investigators at the Mayo Clinic conducted two double blind, placebo controlled trials using 10 grams ascorbate daily to treat patients with advanced cancer, and found no effect. Based on these data, physicians were strongly advised to not use ascorbic acid in cancer treatment. In light of our extensive bioavailability data, we reviewed the experiments of Cameron and colleagues, and the Mayo Clinic investigators. We were astonished to recognize that the Cameron-associated patients received IV and oral ascorbic acid, but the Mayo Clinic-associated patients received only oral ascorbic acid. Thus, comparisons between the treatment groups were invalid, and the issue of ascorbic acid in cancer treatment needed re-evaluation. Based on our bioavailability data and pharmacokinetics modeling, intravenous ascorbic acid dosing can produce plasma concentrations as much as 70 fold higher than maximally tolerated oral doses. In vitro, pharmacologic ascorbic acid concentrations that are easily achieved in humans kill cancer but normal cells. Killing is mediated by extracellular ascorbic acid, its oxidation to ascorbate radical, and protein-dependent formation of hydrogen peroxide. To detect hydrogen peroxide without ascorbate interference, experiments required specialized chemical synthesis of peroxyxanthones, not commercially available. Based on the obtained data, we proposed and validated in vivo the hypothesis that pharmacologic ascorbic acid is a pro-drug for preferential formation of ascorbate radical in the extravascular space, but not blood. Again, in vivo experiments were dependent on synthesis of peroxyxanthones. Concurrently, we developed a hypothesis explaining why cancer but not normal cells are sensitive to ascorbate mediated death via hydrogen peroxide formation. Hydrogen peroxide may selectively kill cancer cells by one of at least three mechanisms: activation of poly ADP-ribose polymerase (PARP);inability to detoxify hydrogen peroxide because of limited reducing equivalents for glutathione dependent peroxidases;and direct mitochondrial toxicity. Each of these mechanisms will deplete intracellular ATP, a hallmark of hydrogen peroxide-mediated cell killing. Experiments exploring these concepts are underway. Other current efforts are focused on: investigation of pharmacologic ascorbic acid as an agent to inhibit tumor growth in animal models;in vivo imaging of hydrogen peroxide;completion of a phase I clinical trial, with collaborators at McGill University;and characterization of clinical usage patterns and safety.